Cooperation of Sox4 with β-catenin/p300 complex in transcriptional regulation of the Slug gene during divergent sarcomatous differentiation in uterine carcinosarcoma.
Cooperation of Sox4 with β-catenin/p300 complex in transcriptional regulation of the Slug gene during divergent sarcomatous differentiation in uterine carcinosarcoma.
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DOI：
10.1186/s12885-016-2090-y
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发表时间：
2016-02-03
期刊：
影响因子：
3.8
通讯作者：
Saegusa M
中科院分区：
文献类型：
--
作者：
Inoue H;Takahashi H;Hashimura M;Eshima K;Akiya M;Matsumoto T;Saegusa M
子宫癌肉瘤是与上皮-间充质转化(EMT)相关的癌症的真实例子，它表现出癌症干细胞(CSC)样的特征。SOX和β-catenin信号转导在调节子宫肌间充质干细胞的特性中起着关键作用，但对它们在腰椎上皮细胞肿瘤发生中的作用却知之甚少。在此，我们重点研究SOX/β-连环蛋白通路在UCSs中的功能作用。用3株子宫内膜癌(Em-Ca)细胞株进行EMT/CSC实验和基因转染实验。对32例UCSs进行免疫组织化学染色。在无血清间充质干细胞培养液中培养的EM-Ca细胞，通过下调E-钙粘附素和上调β-连环蛋白的靶基因--slug的表达，使细胞的形态发生了向内胚层转变的转变。细胞还表现出CSC特性，乙醛脱氢酶(ALDH)1高活性群体和球体形成增加，Sox4、Sox7和Sox9表达上调。在这些SOX因子中，SOX4的过表达显著地导致了SLUG启动子的反式激活，并且SOX7或SOX9的共转染进一步增强了这种作用。SOX4还可以通过与β-连环素和p300形成转录复合体来促进β-连环素介导的slug基因的转录，而不依赖于TCF4的状态。在临床样本中，肉瘤成分中的核β-连环蛋白和Slug评分均显著高于癌性成分，且与SOX4、SOX7和SOX9评分呈正相关。这些结果提示，Sox4、Sox7和Sox9可能通过与β-catenin/p300信号通路协同作用，通过转录调控Slug基因，参与调节肌间质瘤/血管干细胞的性质，促进UCSs肉瘤成分的发育。本文的在线版本(doi：10.1186/s12885-0162090-y)包含补充材料，授权用户可以使用。
Uterine carcinosarcoma (UCS) represents a true example of cancer associated with epithelial-mesenchymal transition (EMT), which exhibits cancer stem cell (CSC)-like traits. Both Sox and β-catenin signal transductions play key roles in the regulation of EMT/CSC properties, but little is known about their involvement in UCS tumorigenesis. Herein, we focused on the functional roles of the Sox/β-catenin pathway in UCSs. EMT/CSC tests and transfection experiments were carried out using three endometrial carcinoma (Em Ca) cell lines. Immunohistochemical investigation was also applied for a total of 32 UCSs. Em Ca cells cultured in STK2, a serum-free medium for mesenchymal stem cells, underwent changes in morphology toward an EMT appearance through downregulation of E-cadherin, along with upregulation of Slug, known as a target gene of β-catenin. The cells also showed CSC properties with an increase in the aldehyde dehydrogenase (ALDH) 1high activity population and spheroid formation, as well as upregulation of Sox4, Sox7, and Sox9. Of these Sox factors, overexpression of Sox4 dramatically led to transactivation of the Slug promoter, and the effects were further enhanced by cotransfection of Sox7 or Sox9. Sox4 was also able to promote β-catenin-mediated transcription of the Slug gene through formation of transcriptional complexes with β-catenin and p300, independent of TCF4 status. In clinical samples, both nuclear β-catenin and Slug scores were significantly higher in the sarcomatous elements as compared to carcinomatous components in UCSs, and were positively correlated with Sox4, Sox7, and Sox9 scores. These findings suggested that Sox4, as well as Sox7 and Sox9, may contribute to regulation of EMT/CSC properties to promote development of sarcomatous components in UCSs through transcriptional regulation of the Slug gene by cooperating with the β-catenin/p300 signal pathway. The online version of this article (doi:10.1186/s12885-016-2090-y) contains supplementary material, which is available to authorized users.